Clinical Guidance

Although inter- and intrafamilial variation is common, some generalities can be made regarding genotype-phenotype correlations. COL2A1-related Stickler syndrome. Pathogenic variants in COL2A1 that cause Stickler syndrome are typically loss-of-functions variants associated with haploinsufficiency of type II collagen (e.g., nonsense variants, small deletions/duplications, splicing variants that cause a frameshift). COL2A1 pathogenic variants that do not result in a premature stop codon and/or nonsense-mediated RNA decay but have a dominant-negative effect are causative for the more severe type II collagenopathies such as spondyloepiphyseal dysplasia congenita . These are usually missense variants causing a glycine substitution in the triple helical domain.

Source: GeneReviews — "Stickler Syndrome"

Penetrance

Penetrance is complete.

Source: GeneReviews — "Stickler Syndrome"

Diagnostic Criteria

No consensus clinical diagnostic criteria for Stickler syndrome have been published.

Suggestive Findings

Stickler syndrome should be suspected in individuals with a combination of the following clinical and radiographic findings.

Clinical findings

• Cleft palate (open cleft, submucous cleft, or bifid uvula)

• Characteristic facial features including malar hypoplasia, broad or flat nasal bridge, and micro- or retrognathia

• Ocular manifestations including high myopia, vitreous abnormalities, cataracts, and/or retinal abnormalities

• Sensorineural hearing loss with or without conductive hearing loss

• Osteoarticular manifestations with joint pain in childhood and early-onset degenerative joint disease in adulthood

Imaging findings

Source: GeneReviews — "Stickler Syndrome"

Differential Diagnosis

A number of disorders have features that overlap with those of Stickler syndrome. Pierre Robin sequence. Approximately one third of individuals with Pierre Robin sequence have an underlying syndrome, of which Stickler syndrome is the most common . Binder syndrome (maxillonasal dysplasia) (OMIM 155050). Affected individuals typically have an unusually flat, underdeveloped midface (midfacial hypoplasia), with an abnormally short nose and flat nasal bridge and underdeveloped upper jaw. Binder syndrome may not represent a distinct disease entity or syndrome but rather a developmental anomaly that can be seen in several syndromes such as Stickler syndrome, campomelic dysplasia, and chondrodysplasia punctata. Table 4. Genes of Interest in the Differential Diagnosis of Stickler Syndrome

Management Guidelines

No clinical practice guidelines for Stickler syndrome have been published. Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with Stickler syndrome, the evaluations summarized (if not performed as part of the evaluation that led to the diagnosis) are recommended. Table 5. Stickler Syndrome: Recommended Evaluations Following Initial Diagnosis

Source: GeneReviews — "Stickler Syndrome"

Clinical Guidance

Affected individuals should be advised to avoid activities that may lead to traumatic retinal detachment (e.g., contact sports). Some physicians recommend avoiding physical activities that involve high impact to the joints to delay the onset of the arthropathy. While this recommendation seems logical, there are no data to support it.

Source: GeneReviews — "Stickler Syndrome"

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Source: GeneReviews — "Stickler Syndrome"

Surveillance Guidelines

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in are recommended.

Table 7.

Stickler Syndrome: Recommended Surveillance

System/Concern | Evaluation | Frequency

Eyes | Exam by vitreoretinal specialist | Annually

Hearing

| Audiologic eval

Orthopedic

| Clinical radiographic assessment for joint spine manifestations | As needed

Source: GeneReviews — "Stickler Syndrome"